Mechanisms contributing to the ability of norepinephrine (NE) to enhance arteriolar myogenic responsiveness were studied in the rat cremaster muscle. Anesthetized rats were enclosed in an airtight box that could be pressurized to increase intravascular pressure in the cremaster, which was exteriorized into a tissue bath. Vessel diameter, intravascular pressure, and red cell velocity were measured in the first-order (1A) arteriole during box pressure increases of 10, 20, and 30 mmHg. Control arterioles [diameter = 113 +/- 3 (SE) microns] did not exhibit myogenic constriction in response to step increases in intravascular pressure (e.g., + 30 mmHg, diameter = 122 +/- 5 microns), whereas after 25% constriction with NE (diameter = 85 +/- 2 microns) arterioles exhibited significant myogenic constriction (e.g., +30 mmHg, diameter = 70 +/- 4 microns). The NE effect on myogenic reactivity was augmented by Ca2+ channel agonists and inhibited by antagonists, suggesting a role for voltage-operated Ca2+ channels. In contrast to NE, exposure to KCl (30 mM) did not enhance myogenic responsiveness, suggesting that factors in addition to voltage-operated channels were involved in the NE effect. The protein kinase C (PKC) activator indolactam (1 microM) was found to increase vascular tone in the 1A arterioles (diameter = 109 +/- 6 to 89 +/- 7 microns) and to induce significant myogenic responsiveness similar to that produced by NE (e.g., +30 mmHg, diameter = 65 +/- 9 microns). Staurosporine (0.1 microM) and calphostin C (1 microM), inhibitors of PKC, significantly attenuated the NE-induced myogenic response.(ABSTRACT TRUNCATED AT 250 WORDS)